Recent studies have highlighted the significance of Fc-FcR interactions to achieve in vivo protection for neutralizing antibodies to HIV and other viruses or bacterial toxins through mechanisms including ADCC and ADCVl. We have defined both the amino acid and glycan requirements for IgG Fc binding to Fc?Rs and developed animal models based on novel strains of Fc?R humanized mice to determine the impact of amino acid and glycan modifications of human IgGs on their in vivo function. Despite the growing appreciation for the importance of Fc mediated effector functions to the in vivo potency of antibody mediated viral neutralization for bNAbs to HIV, no systematic studies have been performed to determine the optimal Fc structure that will result in these activities. We will characterize the contributions of Fc structure and effector functions to the activities of the bNAbs isolated by Nussenzweig and generate modified bNAbs optimized for Fc effector functions. These re-engineered bNAbs will be tested in vitro for neutralization, ADCC and ADCVBI and, in collaboration with Nussenzweig, in a novel in vivo neutralization assay, based on the TZM-bl assay in mice that carry human Fc?R. In collaboration with Bjorkman we will obtain structural information for these modified antibody Fc's, alone and in complex to specific Fc?Rs, These data will direct the generation of additional variants to further enhance Fc-Fc?R function. These studies will result in the generation of novel, bNAbs optimized for both neutralization and effector function and provide the framework to develop immunization strategies that will result in bNAbs with optimal effector properties.
The generation of effective anti-HIV immunity remains a formidable challenge to global health. Through the studies proposed in this subproject we will investigate mechanisms to enhance immunogenicity of potential target antigens to generate neutralizing antibodies and to engineer neutralizing antibodies to augment their in vivo activity.
| Wang, Haoqing; Barnes, Christopher O; Yang, Zhi et al. (2018) Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion. Cell Host Microbe 24:579-592.e4 |
| Stadtmueller, Beth M; Bridges, Michael D; Dam, Kim-Marie et al. (2018) DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions. Immunity 49:235-246.e4 |
| Gautam, Rajeev; Nishimura, Yoshiaki; Gaughan, Natalie et al. (2018) A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat Med 24:610-616 |
| Cohn, Lillian B; da Silva, Israel T; Valieris, Renan et al. (2018) Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation. Nat Med 24:604-609 |
| Horwitz, Joshua A; Bar-On, Yotam; Lu, Ching-Lan et al. (2017) Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo. Cell 170:637-648.e10 |
| Nishimura, Yoshiaki; Gautam, Rajeev; Chun, Tae-Wook et al. (2017) Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543:559-563 |
| Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Anti-retroviral antibody Fc?R-mediated effector functions. Immunol Rev 275:285-295 |
| Gristick, Harry B; Wang, Haoqing; Bjorkman, Pamela J (2017) X-ray and EM structures of a natively glycosylated HIV-1 envelope trimer. Acta Crystallogr D Struct Biol 73:822-828 |
| Bournazos, Stylianos; Wang, Taia T; Dahan, Rony et al. (2017) Signaling by Antibodies: Recent Progress. Annu Rev Immunol 35:285-311 |
| Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233 |
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